Genomic and clinical correlates of belzutifan treatment in renal cell carcinoma (RCC): A retrospective analysis of 150 RCC patients.
Year: 2026
Type: conference-abstract
Abstract: 4541 Background: Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor approved for RCC that targets a central driver in RCC pathogenesis; however, predictive biomarkers of response remain poorly defined. Methods: Comprehensive DNA (592-gene panel or whole exome) and RNA (whole transcriptome) sequencing were performed by Caris Life Sciences on RCC samples. Clear cell RCC and RCC-NOS with VHL mutations were included. Belzutifan time on treatment (ToT) was derived from insurance claims, and patients were classified as responders or non-responders using the median ToT. Results: A total of 150 belzutifan-treated RCC tumors were included in the analysis, of which 29% were primary kidney tumors and the remainder were from metastatic sites. The study population was classified as responders (n=57) or non-responders (n=93) using a median time on treatment of 85 days (95% CI: 71–114). Baseline characteristics were similar, except responders were younger (median age 57 vs 64 years, p=0.007). Transcriptomic analysis showed similar HIF-2α (median 7.78 vs 7.61) and CA9 (4.82 vs 4.54) expression between responders and non-responders without statistical significance. Responders showed enrichment of PTEN (15.8% vs. 3.3%, p=0.03) and PIK3R1 alterations (7.0% vs. 0.0%, p=0.04). Responders demonstrated numerically higher frequencies of PBRM1 (54.4% vs. 44.3%, p=0.46) and PIK3CA mutations (8.8% vs. 3.3%, p=0.24). Alterations in DNA damage response genes were also numerically more common among responders, including TP53 (14.0% vs. 4.9%, p=0.11) and ATM (3.5% vs. 1.6%, p=0.56), although none of these differences reached statistical significance. In contrast, non-responders exhibited numerically higher frequencies of BAP1 (18.0% vs. 8.8%, p=0.10), SETD2 (26.2% vs. 19.3%, p=0.27), and ARID1A (5.1% vs. 1.8%, p=0.30), all of which were also not statistically significant. Conclusions: HIF2-α RNA expression alone does not predict belzutifan response in RCC. Responders demonstrated alterations in PBRM1, PI3K/AKT/mTOR, and DNA damage response genes, while non-responders showed numerically higher frequencies of chromatin remodeling mutations including BAP1 and SETD2. Study limitation included small sample size and short follow-up. Larger datasets are required to validate these findings.
Source: Journal of Clinical Oncology
Authors: Harshitha Reddy Dudipala, Yu-Wei Chen, Shayan S. Nazari, Andrew Elliott, Ninad Kulkarni, Rashad Nawfal, Liliana Ascione, Marc Machaalani, David F. McDermott, Sabina Signoretti, Pedro C. Barata, Brent S. Rose, Aditya Bagrodia, Neeraj Agarwal, Sumanta Kumar Pal, Toni K. Choueiri, Rana R. McKay
Institutions: Moores Cancer Center, Caris Life Sciences (United States), Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, University Hospitals Seidman Cancer Center, Case Western Reserve University, University of California San Diego, University of Utah, Huntsman Cancer Institute, City Of Hope National Medical Center
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7162533071
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